The Polycystic

Ovary Syndrome

Section Editors
Deborah Cotton, MD, MPH
Darren Taichman, MD
Sankey Williams, MD
Science Writer
Jennifer F. Wilson

Diagnosis

page ITC2-2

Treatment

page ITC2-9

Practice Improvement

page ITC2-14

Tool Kit

page ITC2-14

Patient Information

page ITC2-15

CME Questions

page ITC2-16

The content of In the Clinic is drawn from the clinical information and education
resources of the American College of Physicians (ACP), including PIER (Physicians
Information and Education Resource) and MKSAP (Medical Knowledge and SelfAssessment Program). Annals of Internal Medicine editors develop In the Clinic
from these primary sources in collaboration with the ACPs Medical Education and
Publishing divisions and with the assistance of science writers and physician writers. Editorial consultants from PIER and MKSAP provide expert review of the content. Readers who are interested in these primary resources for more detail can
consult http://pier.acponline.org, http://www.acponline.org/products_services/
mksap/15/?pr31, and other resources referenced in each issue of In the Clinic.
CME Objective: To revuew current evidence for the diagnosis and treatment of the
polycystic ovary syndrome.
The information contained herein should never be used as a substitute for clinical
judgment.
2010 American College of Physicians

In theClinic

In the Clinic

he polycystic ovary syndrome (PCOS) is a common hormone disorder affecting women of reproductive age. Prevalence estimates vary
between 5% and 15%, depending on the criteria. In recent years,
recognition and understanding of the condition have improved significantly,
but it is still widely underdiagnosed (1). The European Society for Human
Reproduction and Embryology and the American Society for Reproductive
Medicine (ESHRE/ASRM) have recommended that PCOS be diagnosed
only after excluding other medical conditions that cause irregular menstrual
cycles and androgen excess and only if at least 2 of the following are present:
oligoovulation or anovulation, elevated levels of circulating androgens or
clinical manifestations of androgen excess, and polycystic ovaries on ultrasonography (2). While these criteria are the most widely used, there are 2
other criteria that are favored by other expertsthe so-called NIH criteria
(3) and the Androgen Excess Society criteria (4).

1. March WA, Moore VM,

Willson KJ, Phillips DI,
Norman RJ, Davies
MJ. The prevalence of
polycystic ovary syndrome in a community sample assessed
under contrasting diagnostic criteria.
Hum Reprod.
2010;25:544-51.
[PMID:19910321]
2. Rotterdam
ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group.
Revised 2003 consensus on diagnostic criteria and long-term
health risks related to
polycystic ovary syndrome. Fertil Steril.
2004;81:19-25.
[PMID:14711538]
3. Zawadzki JK, Dunaif
A. Diagnostic criteria
for polycystic ovary
syndrome: towards a
rational approach. In:
Dunaif A, Givens JR,
Haseltine FP, Merriam
GE (eds). Polycystic
Ovary Syndrome.
Current Issues in Endocrinology and Metabolism. Boston:
Blackwell Scientific
Publications;
1992:377.
4. Azziz R, Carmina E,
Dewailly D, et al; Task
Force on the Phenotype of the Polycystic
Ovary Syndrome of
The Androgen Excess
and PCOS Society.
The Androgen Excess
and PCOS Society criteria for the polycystic ovary syndrome:
the complete task
force report. Fertil
Steril. 2009;91:456-88.
[PMID:18950759]
5. Nestler JE. Metformin
for the treatment of
the polycystic ovary
syndrome. N Engl J
Med. 2008;358:47-54.
[PMID:18172174]
6. Wild RA, Carmina E,
Diamanti-Kandarakis
E, et al. Assessment of
cardiovascular risk
and prevention of
cardiovascular disease in women with
the polycystic ovary
syndrome: a consensus statement by the
Androgen Excess and
Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab.
2010;95:2038-49.
[PMID:20375205]

Pathophysiologically, PCOS results from complex, and not yet fully understood, interactions between the ovaries, androgens, gonadotropins, and
insulin (5). Often in PCOS, follicles fail to grow to a size that triggers ovulation and multiple small cysts develop and accumulate in the ovary, resulting
in a hormone imbalance . Polycystic ovaries are not, however, necessary to
make a diagnosis of PCOS, and the presence of polycystic ovaries alone does
not establish a diagnosis of PCOS.
The effects of PCOS range from mild to severe and include infertility, hirsutism, acne, alopecia, and insulin resistance. The disorder also seems to increase the long-term risk for various diseases, including type 2 diabetes and
dyslipidemia (see the Box: Lifelong Health Complications).

Diagnosis

2011 American College of Physicians

Who is at risk for PCOS?

While the condition can develop in
any woman, certain factors seem to
increase risk. A family history of
the condition increases the risk for

PCOS, and certain ethnicities and

races experience a higher prevalence of the syndrome (8). Research
into genetic susceptibilities is
ongoing (8-10).

Lifelong Health Complications

Reproductive
Prenatal or childhood: Premature adrenarche, early menarche
Adolescence, reproductive years: Menstrual irregularity, hirsutism, acne, infertility,
endometrial cancer, miscarriage, pregnancy complications
Postmenopause: In postmenopausal women with a history of PCOS, circulating androgens
may continue to be higher than in postmenopausal women without PCOS and may be
associated with hyperlipidemia and increased risk for vascular disease (6)

Metabolic
Prenatal or childhood: Abnormal fetal growth
Adolescence, reproductive years: Obesity, impaired glucose tolerance, insulin resistance,
dyslipidemia, type 2 diabetes, the metabolic syndrome
Postmenopause: Obesity, impaired glucose tolerance, insulin resistance, dyslipidemia, type 2
diabetes

Other
Adolescence, reproductive years: Sleep apnea, fatty liver, depression
Postmenopause: Cardiovascular disease
Data from references 6 and 7.

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1 February 2011

Women who are obese (using a

body mass index [BMI] criteria of
> 30 kg/m2 ) have an increased risk
for PCOS, and conversely, at least
one third of women with PCOS
are obese. Development of obesity
may unmask or exacerbate the biochemical and clinical abnormalities
that characterize the disorder (11).

Having polycystic ovaries alone

does not mean that a woman has
PCOS. An estimated 20% of
women with polycystic ovaries have
no symptoms (13).

Impaired glucose tolerance is common, occurring in approximately one

third of women with the disorder. An
estimated 10% of women with the
syndrome followed in a large prospective cohort study developed type 2 diabetes by the time they were in their
40s. Type 2 diabetes is more common
in obese women with PCOS than in
lean women with PCOS (12).

The symptoms, signs, and biochemical features of PCOS vary greatly

among women, and they may
change in individuals over time. Clinicians should consider PCOS in
women with clinical signs of excess
androgen (hyperandrogenemia),
menstrual irregularity, infertility, and
obesity, particularly in the abdomen
(14) (Table 1).

What symptoms and signs should

prompt clinicians to consider the
diagnosis of PCOS?

Table 1. History and Physical Examination Elements for PCOS

Category

Element

Notes

History

Menstrual irregularity

Irregular menses begin at menarche, and a normal pattern is

never established; chronic anovulation results in oligomenorrhea or amenorrhea and the absence of ovulatory symptoms
First appears during early menarchal years and gradually worsens; the FerrimanGallwey scoring system may be used to document the degree of hirsutism; the psychosocial implications
are important in developing treatment goals
Begins at menarche and may be more severe than in women
without PCOS
There is a strong familial association both with PCOS and other
manifestations of insulin resistance (e.g., diabetes, hypertension, CAD)
It is essential to elicit other cardiovascular risk factors to
determine overall morbidity risk
In addition to the possibility of requiring assistance to become
pregnant, women with PCOS are more likely to have their
pregnancies complicated by gestational diabetes and
hypertension; the womans desire for pregnancy affects
treatment choice
Whether risk for hypertension in these women independent of
body weight is increased is controversial; nonetheless, it is important for assessing cardiovascular risk

Hirsutism

Acne
Family history

Other cardiovascular
risk factors
Pregnancy history and
desire for pregnancy in
future

Physical examination

Blood pressure

Body mass index

Waist-to-hip ratio
Hirsutism

Acne
Acanthosis nigricans
Alopecia

A waist-to-hip ratio >0.85 and a waist circumference >100 cm

are associated with cardiovascular morbidity
Location and severity of hirsutism should be recorded; ethnicity
must be taken into account when assessing a normal pattern;
generally, terminal hair on the sternum, upper abdomen, and
upper back suggest hyperandrogenemia compared with hair on
the upper lip and areolae
Severity and location should be documented
Raised, velvety brown discoloration on the nape of neck, axilla,
knuckles, and elbows is seen in all hyperinsulinemic syndromes
Although severe alopecia is uncommon, male-pattern baldness
may be detected

CAD = coronary artery disease; PCOS = the polycystic ovary syndrome.

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7. Norman RJ, Dewailly

D, Legro RS, Hickey
TE. Polycystic ovary
syndrome. Lancet.
2007;370:685-97.
[PMID:17720020]
8. Goodarzi MO,
Quiones MJ, Azziz R,
Rotter JI, Hsueh WA,
Yang H. Polycystic
ovary syndrome in
Mexican-Americans:
prevalence and association with the
severity of insulin resistance. Fertil Steril.
2005;84:766-9.
[PMID:16169421]
9. Menke MN, Strauss JF
3rd. Genetic approaches to polycystic ovarian syndrome.
Curr Opin Obstet Gynecol. 2007;19:355-9.
[PMID:17625418]
10. Ewens KG, Stewart
DR, Ankener W, et al.
Family-based analysis of candidate
genes for polycystic
ovary syndrome. J
Clin Endocrinol
Metab.
2010;95:2306-15.
[PMID:20200332].
11. Barber TM, McCarthy
MI, Wass JAH, Franks
S. Obesity and polycystic ovary syndrome. Clin Endocrinol. 2006;
65:137-45.
[PMID:16886951]
12. Legro RS, Kunselman
AR, Dodson WC,
Dunaif A. Prevalence
and predictors of risk
for type 2 diabetes
mellitus and impaired glucose tolerance in polycystic
ovary syndrome: a
prospective, controlled study in 254
affected women. J
Clin Endocrinol
Metab. 1999;84:1659. [PMID:9920077]
13. Balen AH, Rutherford AJ. Managing
anovulatory infertility and polycystic
ovary syndrome.
BMJ. 2007;335:663-6.
[PMID:17901517]
14. George K, Alberti
KG, Zimmet P, Shaw
J, for the IDF Epidemiology Task
Force Consensus
Group. The metabolic syndromea new
worldwide definition. Lancet.
2005;366:10591062

2011 American College of Physicians

While regular menses usually

develop within a few years after
menarche, women with PCOS
have menstrual irregularity often
beginning at menarche and typically continuing for many years (15).
Asking about symptom onset can
help differentiate PCOS from other causes of menstrual irregularities,
and clinicians should strongly consider other diagnoses to be more
likely if symptoms began years after
puberty or have suddenly worsened.

15. van Hooff MH,

Voorhorst FJ, Kaptein
MB, et al. Endocrine
features of polycystic ovary syndrome
in a random population sample of 14-16
year old adolescents.
Hum Reprod.
1999;14:2223-9.
[PMID:10469684]
16. Legro RS. Polycystic
ovary syndrome.
Phenotype to genotype. Endocrinol
Metab Clin North
Am. 1999;28:379-96.
[PMID:10352924]
17. Balen AH, Conway
GS, Kaltsas G, et al.
Polycystic ovary syndrome: the spectrum of the disorder
in 1741 patients.
Hum Reprod.
1995;10:2107-11.
[PMID:8567849]
18. Carmina E, Koyama
T, Chang L, Stanczyk
FZ, Lobo RA. Does
ethnicity influence
the prevalence of
adrenal hyperandrogenism and insulin
resistance in polycystic ovary syndrome? Am J Obstet
Gynecol.
1992;167:1807-12.
[PMID:1471702]
19. Shapiro J. Clinical
practice. Hair loss in
women. N Engl J
Med. 2007; 357:
1620-30.
[PMID:17942874]
20. Lord J, Thomas R,
Fox B, Acharya U,
Wilkin T. The central
issue? Visceral fat
mass is a good
marker of insulin resistance and metabolic disturbance in
women with polycystic ovary syndrome. Br J Obstet
Gynaecol.
2006;113:1203-9.
[PMID:16753044]

2011 American College of Physicians

Menstrual irregularity may consist

of oligomenorrhea (i.e., menstruation that occurs less frequently than
normal or that is very light) or
amenorrhea (i.e., the absence of
menstruation). The menstrual pattern may improve with weight loss
or worsen with weight gain, or it
may improve spontaneously.
Infertility

PCOS is the most common cause

of anovulatory infertility, and up
to 74% of women with PCOS
were found in 1 study to have
some degree of infertility (16).
Thus, clinicians should consider
PCOS in all women who present
with this sign.
Hyperandrogenemia

Signs of excess androgen are common in PCOS. Hirsutism, appearing as male-type hair growth in
women on the face, back, or chest,
occurs in most women with PCOS
(17). The disorder is equally prevalent in different countries/regions
around the world. However, the expression of symptoms and signs, or
phenotype, differs. Comparative
studies have shown that the prevalence of hirsutism in PCOS varies
with ethnicity, and is higher in
Hispanic and Italian women in the
United States than in those of
Japanese origin (18).

associated with PCOS. Acanthosis

nigricans, which is seen in all hyperinsulinemic syndromes, may
develop and consists of raised, velvety, brown discoloration on the
nape of the neck, axilla, knuckles,
and elbows. The hyperandrogenemic symptoms may worsen slowly,
especially if body weight increases.
Other virilizing features, such as
clitoromegaly and increased muscle bulk, are far less common and
suggest an alternative diagnosis.
Again, if symptoms began years
after puberty or suddenly worsen,
other diagnoses are more likely
than PCOS.
Even if hyperandrogenemic symptoms are not a concern at presentation, they may become more
worrisome as a woman ages. Hyperandrogenemia can seriously affect
self-esteem, and women with severe
hirsutism or acne may benefit from
expert consultation to ameliorate
these manifestations.
Abdominal obesity

Many women with PCOS are

obese, and women with abdominal
obesity are more likely to have
PCOS. The prevalence of obesity
in PCOS depends greatly on the
population studied. Abdominal
obesity is associated with insulin
resistance and cardiovascular risk,
and it is an important predictor of
long-term morbidity. Thus, an increased waist circumference should
lead to a directed history and physical examination for the other aspects of PCOS (14, 20).
Other signs and symptoms

Acne, particularly that which began with puberty, and alopecia

(19), which can even present
as male-pattern baldness, are
other signs of excess androgen

Women with PCOS may have an

increased risk for hypertension
and hyperlipidemia, as well as an
increased risk for cardiovascular
disease (21). Prevalence of obstructive sleep apnea may also be
higher than in the general population (22), and women with PCOS
may also have high levels of depression and diminished quality of
life (23, 24).

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What proportion of women

with oligomenorrhea have PCOS,
and what is the menstruation
pattern?
Oligomenorrhea is a common
symptom in women with PCOS,
and most obese women with
oligomenorrhea have PCOS (25).
Women with oligomenorrhea
menstruate less frequently than
normal, with 35 days typically
elapsing between cycles and only
4 to 9 periods occurring per year.
Occasionally, they menstruate on
a more normal cycle, but their
menses are very light. Some
women with PCOS do not menstruate at all.
Alternate causes of oligomenorrhea
and amenorrhea should be ruled
out, and these include chronic illness; eating disorders or poor nutrition; extremely low weight; emotional stress; excessive exercise;
thyroid dysfunction; illegal use of
anabolic steroids among athletes;
and estrogen-secreting and pituitary tumors, the most common being prolactinomas.
How does PCOS affect fertility?
In women with PCOS, the
growth of follicles that trigger
the luteinizing hormone (LH)
surge, and ovulation is arrested.
As a result, ovulation does not
regularly occur and many women
with PCOS experience difficulty
becoming pregnant (see the Box:
PCOS and Infertility). Studies

have estimated that PCOS

accounts for up to 90% of
cases of infertility caused by
anovulation (26).
Women with PCOS who do become pregnant are more likely to
have complications, including higher
risk for gestational diabetes, preterm
labor, and pregnancy-induced high
blood pressure and preeclampsia (27)
(see the Box: PCOS and Pregnancy
Care). They may also have an increased risk for miscarriage; however,
the evidence is less clear.
Which laboratory tests are useful
in diagnosis?
Various laboratory tests can be
helpful for diagnosing PCOS
(Table 2). In general, serum androgen measurements are used to
confirm hyperandrogenemia,
which is 1 of the 3 diagnostic criteria for PCOS of which 2 are required for diagnosis. Hyperandrogenemia occurs in PCOS from
excess ovarian and adrenal androgen production. Most women
with the disorder have increased
total and free testosterone levels,
and the free testosterone level may
be significantly increased in obese
women because of the effects of
increased body weight on lowering
the level of sex hormonebinding
globulin. The androstenedione
level is also increased in PCOS
and may be slightly more sensitive; however, it is not often used
in clinical practice.
PCOS and Pregnancy Care

PCOS and Infertility

Infertility is common in PCOS
Women with PCOS and fertility
concerns should be referred to a
specialist
A full infertility workup of both
partners should precede drug therapy
for infertility
Lifestyle modifications, especially weight
loss if obese, may improve fertility
Drug treatments as well as surgical
approaches to infertility can be used
Pregnancy can be achieved in many if
not most women with PCOS

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Annals of Internal Medicine

Women with PCOS should plan their

pregnancies
Women with PCOS, like all women,
should receive folate supplementation
before pregnancy occurs
Women with diabetes should try to
achieve optimal glycemic control
before pregnancy
Antenatal screening for diabetes and
hypertension should be performed
Closer follow-up during pregnancy
may be needed for women with PCOS
to avoid and manage pregnancy
complications

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21. Alexander CJ, Tangchitnob EP, Lepor

NE. Polycystic ovary
syndrome: a major
unrecognized cardiovascular risk factor in women. Rev
Obstet Gynecol.
2009;2:232-9.
[PMID:20111659]
22. Tasali E, Van Cauter
E, Ehrmann DA. Polycystic ovary syndrome and obstructive sleep apnea.
Sleep Med Clin.
2008;3:37-46.
[PMID:19255602]
23. Barnard L, Ferriday
D, Guenther N, et al.
Quality of life and
psychological well
being in polycystic
ovary syndrome
Hum. Reprod.
2007;22:2279-86.
[PMID:17537782]
24. Kerchner A, Lester
W, Stuart SP, Dokras
A. Risk of depression
and other mental
health disorders in
women with polycystic ovary syndrome: a longitudinal study. Fertil Steril.
2009; 91 (1) :207-12.
[PMID:18249398]
25. Franks S, White DM.
Prevalence of and
etiological factors in
polycystic ovarian
syndrome. Ann N Y
Acad Sci.
1993;687:112-4.
[PMID:8323165]
26. Balen AH, Michelmore K. What is
polycystic ovary syndrome? Are national
views important?
Hum Reprod.
2002;17:2219-27.
[PMID:12202405]
27. Legro R. Pregnancy
considerations in
women with polycystic ovary syndrome. Clin Obstet
Gynecol.
2007;50:295-304.
[PMID:17304043]

2011 American College of Physicians

Table 2. Laboratory and Other Studies for PCOS

Test

Notes

Serum testosterone
Androstenedione

Free (bioavailable) and total testosterone levels

Not as common a test but may have slightly better sensitivity in
ultrasound-proven PCOS
High normal LH and normal FSH with ratio >2 consistent with
diagnosis
May be slightly elevated in PCOS
Although usually increased, not helpful for diagnosis;
if markedly increased, consider adrenal neoplasia
Approximately 50% of women with glucose intolerance have a
normal fasting glucose level and an elevated level 2 hours after
a 75-g glucose load. However, the clinical significance and
treatment benefits of isolated postprandial hyperglycemia
require further study.
Provides further assessment of cardiovascular risk

LH, FSH
Serum prolactin
DHEAS
Fasting glucose level
and glucose tolerance test

Fasting cholesterol,
triglycerides, and HDL
cholesterol

DHEAS = dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; HDL = high-density

lipoprotein; LH = luteinizing hormone; PCOS = the polycystic ovary syndrome.

28. Robinson S, Rodin

DA, Deacon A,
Wheeler MJ, Clayton
RN. Which hormone
tests for the diagnosis of polycystic
ovary syndrome? Br
J Obstet Gynaecol.
1992;99:232-8.
[PMID:1296589]
29. Koskinen P, Penttil
TA, Anttila L, Erkkola
R, Irjala K. Optimal
use of hormone determinations in the
biochemical diagnosis of the polycystic
ovary syndrome. Fertil Steril. 1996;65:51722. [PMID:8774279]
30. Welt CK, Arason G,
Gudmundsson JA, et
al. Defining constant
versus variable phenotypic features of
women with polycystic ovary syndrome using different ethnic groups
and populations. J
Clin Endocrinol
Metab.
2006;91:4361-8.
[PMID:16940441]
31. Ehrmann DA, Barnes
RB, Rosenfield RL,
Cavaghan MK, Imperial J. Prevalence of
impaired glucose
tolerance and diabetes in women
with polycystic
ovary syndrome. Diabetes Care.
1999;22:141-6.
[PMID:10333916]

2011 American College of Physicians

Dehydroepiandrosterone sulfate
(DHEAS) level is often increased
but some clinicians believe it adds
little to the diagnosis. However, it
may be the only elevated androgen
in some patients, helping to determine that androgen excess is present.
A study that compared LH, follicle-stimulating hormone (FSH), total testosterone,
DHEAS, and androstenedione levels in
women with clinical and radiographic evidence of PCOS found elevated testosterone
and/or androstenedione levels in 78% and
determined that these were the most sensitive markers (4, 28).
Another study found that an aggregate
of LH, FSH, and androstenedione levels
outperformed other markers (29). Scandanavian women with PCOS seem to
have more elevated levels of andro stenedione, and Boston women with
PCOS seem to have more elevated
testosterone (30).

Gonadotropin level is not a sensitive diagnostic test for PCOS, but

it is helpful in ruling out other
causes of anovulation. Elevated
levels of FSH imply ovarian failure
(e.g., premature menopause).
Impaired glucose tolerance is present in 31% to 35% of the PCOS
population (12, 31).
A recent meta-analysis identified 35 relevant
studies and determined that women with
PCOS had increased prevalence of impaired
glucose tolerance (odds ratio [OR], 2.48 [95%
CI, 1.63 to 3.77]; for BMI-matched studies:
OR, 2.54 [CI, 1.44 to 4.47]), type 2 diabetes
(OR, 4.43 [CI, 4.06 to 4.82]; for BMI-matched
studies: OR, 4.00 [CI, 1.97 to 8.10]), and the
metabolic syndrome (OR, 2.88 [CI, 2.40 to
3.45]; for BMI-matched studies: OR, 2.20 [CI,
1.36 to 3.56]), but noted that few studies
have determined their incidence in women
with and without PCOS (32).

These measurements are also used

to rule out androgen-producing
neoplasms. Androgen levels that
greatly exceed the upper range limit
of the assay suggest an androgenproducing neoplasm that requires
further investigation.

The ESHRE-ASRM case definition

of PCOS advised against testing for
insulin resistance by measuring insulin and glucose because the normal
ranges are not well-defined. Insulin
resistance is usually a given, and in itself is not a reason for referral. The
glucoseinsulin ratio is not helpful
and is not used. Most experts suggest
doing a 2-hour glucose tolerance test

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or measuring hemoglobin A1C levels.

The major goal is to rule out glucose
intolerance.
Is an imaging study documenting
cystic ovaries necessary for
diagnosis?
Unless the diagnosis of PCOS is
already clear, clinicians can consider ovarian ultrasonography.
Polycystic ovary morphology on
ultrasonography (preferably transvaginal) is 1 of the 3 diagnostic
criteria in the European Society
for Human Reproduction and
Embryology/American
Society for Reproductive Medicine consensus definition of
PCOS, 2 of which are needed for
diagnosis.
Until recently, the definition of diagnostic features for polycystic ovaries
by ultrasonography was controversial, but recent imaging advances,
such as high-frequency vaginal
probes and image-enhancing software, have improved measurement
capabilities and resolution (7). The
criteria with sufficient specificity and

sensitivity to define polycystic

ovaries are the presence of 12 follicles in each ovary measuring 2 to 9
mm in diameter or increased ovarian
volume (>10 cm3) (33).
What other diagnosis should
clinicians consider when
evaluating a patient for possible
PCOS?
The onset of symptoms is the most
important part of the history for
differentiating PCOS from other
causes of anovulatory menstrual
irregularities. Consider PCOS for
women in whom menstrual irregularity began at menarche and
continued for well over 1 year, although in some women it can take
up to 3 years to achieve normal
menstrual function. If symptoms
began years after puberty or have
suddenly worsened, consider other
diagnoses may be more likely
(Table 3). Excessively high androgen levels may be secondary to adrenal or ovarian neoplasia (34).
Elements of follow-up for women
with PCOS are shown in Table 4.

Table 3. Differential Diagnosis of PCOS

Disease

Characteristics

Notes

Late-onset congenital
adrenal hyperplasia

May have same clinical presentation

as women with PCOS; may be more
virilized than one would expect for
PCOS and may have short stature;
family history may be present

Androgen-producing
neoplasms

Symptoms do not typically occur at

menarche; tend to be more severe and
are progressive over a short period;
tumors may be ovarian or adrenal in origin
May present at any time, although usually
in adulthood (not adolescence); may be
slowly progressive; has symptoms similar
to PCOS in mild cases.
Galactorrhea may or may not be present;
does not usually present at menarche;
hyperandrogenemic symptoms are not
prominent
The possibility of pregnancy must be
considered in all women with amenorrhea
Hypothyroidism can lead to oligomenorrhea
and/or amenorrhea and infertility

A rare condition compared with PCOS; a

screening 17-hydroxy-progesterone level
may suffice; the benefits of diagnosis (other
than symptom management) do not necessarily
outweigh the costs and inconvenience of
performing ACTH-stimulation tests on all
women with PCOS
Androgen levels are markedly elevated;
radiographic investigations are required
to definitively rule out neoplasia

Cushing syndrome

Hyperprolactinemia

Pregnancy
Hypothyroidism

Best test for screening is a 24-hour urinary

free cortisol test; if this is not possible, an
overnight dexamethasone-suppression test
can be performed
Slightly high prolactin levels are seen with
PCOS; if repetitively elevated, an MRI of the
pituitary sella is warranted
Beta-human chorionic gonadotropin should be
measured
Screen with TSH

ACTH = adrenocorticotropic hormone; DHEAS = dehydroepiandrosterone sulfate; MRI = magnetic resonance imaging;
PCOS = the polycystic ovary syndrome; TSH = thyroid-stimulating hormone.

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32. Moran LJ, Misso ML,

Wild RA, Norman RJ.
Impaired glucose
tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary
syndrome: a systematic review and
meta-analysis. Hum
Reprod Update.
2010;16:347-63.
[PMID:20159883]
33. Balen AH, Laven JS,
Tan SL, Dewailly D.
Ultrasound assessment of the polycystic ovary: international consensus
definitions. Hum Reprod Update.
2003;9:505-14.
[PMID:14714587]
34. Carmina E, Oberfield
SE, Lobo RA. The diagnosis of polycystic
ovary syndrome in
adolescents. Am J
Obstet Gynecol.
2010;203:201.e1-5.
[PMID:20435290]
35. Huber-Buchholz
MM, Carey DG, Norman RJ. Restoration
of reproductive potential by lifestyle
modification in
obese polycystic
ovary syndrome: role
of insulin sensitivity
and luteinizing hormone. J Clin Endocrinol Metab.
1999;84:1470-4.
[PMID:10199797]

2011 American College of Physicians

Table 4. Elements of Follow-up for PCOS

Category

Issue

How?

History

Menstrual
pattern

Menstrual
calendar

How often?

Notes

Every 312 months,

If menses are >3 months apart, a Provera challenge and/or oral
depending on clinical contraceptive should be initiated
situation
History
Hyperandrogenic Documentation Every 36 months
Hirsutism is slow to respond to therapy because of the long cycle
symptoms
of acne severity if clinical
of hair follicle development; a minimum of 6 months is
and hirsutism, manifestation is
required to assess clinical efficacy
including
major and an
frequency and indication for
duration of
treatment
topical measures
(e.g., electrolysis)
History
Pregnancy plans Ask!
As clinically
Pregnancies should be planned to ensure medical conditions are optiappropriate
mized and that the woman is not on medication contraindicated in pregnancy
Physical
Weight, waist
Measure
Each visit
Reduction of abdominal obesity is associated with reduction in insulin
examination circumference
resistance and androgen levels
Physical
Blood pressure
Measure
At least annually
Independent risk for cardiovascular disease; however, this is controversial
examination
if associated with PCOS independent of body weight
Physical
Hyperandrogenism Assess hirsutism As clinically
examination
and acne
appropriate
location and
severity
Laboratory
Glucose
Fasting glucose Annually
Although up to 35% of women have elevated 2-hour pc glucose and
data
intolerance
or 2-hour
fasting glucose <7.0, the clinical benefits of treating those diagnosed
glucose
after glucose challenge are not yet clear; clinical utility of insulin
tolerance test
glucose ratios has not been
established
Laboratory
Serum lipids
Fasting total
Every 13 years
To assess cardiovascular risk
data
cholesterol,
triglyceride, and
HDL cholesterol
levels
Laboratory
Liver function
Only if patient is
data
tests
receiving medication
known to affect
these tests
Nondrug
Dietary and
Assess patient As clinically appropriate Offer other health care professional assistance when appropriate
therapy
exercise
readiness to
counseling
make changes
in diet and/or
exercise
Drug therapy Adverse effects Depends on
As clinically appropriate
medication used
HDL = high-density lipoprotein; PCOS = the polycystic ovary syndrome.

36. Pasquali R, Gambineri A, Biscotti D,

et al. Effect of longterm treatment with
metformin added to
hypocaloric diet on
body composition,
fat distribution, and
androgen and insulin levels in abdominally obese
women with and
without the polycystic ovary syndrome.
J Clin Endocrinol
Metab.
2000;85:2767-74.
[PMID:10946879]

2011 American College of Physicians

Diagnosis... The cause of PCOS is unclear, but it seems to involve both genetic
and environmental factors. Obesity increases the risk for PCOS. Clinicians should
consider PCOS in women with menstrual irregularity, infertility, signs of excess
androgen (hyperandrogenemia), and obesity (particularly abdominal). Diagnosis is
made after other medical conditions that cause irregular menstrual cycles and
androgen excess are excluded and if at least 2 of the following are present: oligoovulation or anovulation, elevated levels of circulating androgens or clinical manifestations of androgen excess, and polycystic ovaries on ultrasonography, according to the 2004 ESHRE/ASRM international consensus. The onset of symptoms is
the most important part of the history for differentiating PCOS from other causes
of anovulatory menstrual irregularities. If symptoms began years after puberty or
have suddenly worsened, consider other diagnoses more likely, although a late diagnosis of PCOS is possible. Excessively high androgen levels should alert the clinician to the possibility of adrenal or ovarian neoplasia.

CLINICAL BOTTOM LINE

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Annals of Internal Medicine

1 February 2011

Treatment
What is the role of diet in the
management of patients with PCOS?
Dietary education is required not
only for the immediate benefit of
weight reduction but also for
long-term reduction of cardiovascular risk. Clinicians should encourage overweight patients to
lose a realistic amount of weight
through diet and exercise. Loss of
abdominal fat seems to be crucial
to restore ovulation. Even moderate weight loss of 2% to 5% of
total body weight has been shown
to improve menstrual regularity
and ovulatory function, hirsutism,
insulin sensitivity, and response
to fertility medication (35-38).
It is commonly believed that a
high-protein diet is better for
women with PCOS, and this is
often advocated in diet books
and Web sites. However, a study
comparing a low-calorie, highprotein diet and a low-calorie,
high-carbohydrate diet found
significant weight loss and improvement in reproductive and
metabolic abnormalities in both
groups but no benefit of the
high-protein regimen (39). Patients should be referred to a dietician for dietary modifications.
When is drug therapy appropriate
for management, and what drug
options are available?
Drug therapy is aimed at treating
the symptoms of PCOS. The
choice of drugs depends on the
patients preference and primary
symptoms (Table 5). If infertility is
not the primary concern, then
treatment is aimed at reducing the
undesired effects of excess androgen and restoring regular menses to
prevent endometrial hyperplasia.
Excess androgen

Local measures, such as shaving

and waxing, possibly combined
with topical treatment with the
antiprotozoal eflornithine, which
retards hair growth, may provide

1 February 2011

Annals of Internal Medicine

acceptable results. Topical medications may be useful for treating

acne. A treatment of 2% to 5%
topical minoxidil is recommended
for alopecia (40).

Drug therapy is also useful when

anovulation causes oligomenorrhea or
amenorrhea (after pregnancy has
been excluded). Prolonged amenorrhea increases the risk for endometrial
carcinoma, thus requiring withdrawal
bleeds. In most women who do not
desire pregnancy, oral contraceptives
provide regular menses and prevent
endometrial hyperplasia.

37. Crosignani PG,

Colombo M, Vegetti
W, Somigliana E,
Gessati A, Ragni G.
Overweight and
obese anovulatory
patients with polycystic ovaries: parallel improvements in
anthropometric indices, ovarian physiology and fertility
rate induced by diet.
Hum Reprod.
2003;18:1928-32.
[PMID:12923151]
38. Thomson RL, Buckley JD, Moran LJ, et
al. The effect of
weight loss on antiMllerian hormone
levels in overweight
and obese women
with polycystic
ovary syndrome and
reproductive impairment. Hum Reprod.
2009;24:1976-81.
[PMID:19380385]
39. Stamets K, Taylor DS,
Kunselman A, Demers LM, Pelkman
CL, Legro RS. A randomized trial of the
effects of two types
of short-term
hypocaloric diets on
weight loss in
women with polycystic ovary syndrome. Fertil Steril.
2004;81:630-7.
[PMID:15037413]
40. Azziz R. The evaluation and management of hirsutism.
Obstet Gynecol.
2003;101:995-1007.
[PMID:12738163]
41. Rittmaster RS. Antiandrogen treatment of polycystic
ovary syndrome. Endocrinol Metab Clin
North Am.
1999;28:409-21.
[PMID:10352926]
42. Martin KA, Chang RJ,
Ehrmann DA, et al.
Evaluation and treatment of hirsutism in
premenopausal
women: an endocrine society clinical practice guideline. J Clin
Endocrinol Metab.
2008;93:1105-20.
[PMID:18252793]
43. Diamanti-Kandarakis
E, Baillargeon JP,
Iuorno MJ, Jakubowicz DJ, Nestler JE. A
modern medical
quandary: polycystic
ovary syndrome, insulin resistance, and
oral contraceptive
pills. J Clin Endocrinol Metab.
2003;88:1927-32.
[PMID:12727935]

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2011 American College of Physicians

If local measures do not provide acceptable results or if the symptoms

are moderate to severe, consider prescribing drug therapy. Start with either oral contraceptives alone or combined with an antiandrogen agent,
depending on symptom severity and
patient preference. Oral contraceptives reduce androgen production,
and the addition of an antiandrogen
agent, such as spironolactone, improves clinical results. Antiandrogen
agents should not be used without
oral contraceptives because of the risk
for pregnancy and breakthrough
bleeding. There is little evidence that
one antiandrogen agent is superior to
another (41, 42). Start with an
estrogenprogestin contraceptive for
6 months. If improvement is insufficient, add an antiandrogen, such as
spironolactone. If improvement is
good, continue the estrogen
progestin prescription.
Controversy exists over the effects of
estrogenprogestin contraceptives on
glucose tolerance, and limited evidence suggests that these agents may
worsen insulin resistance and glucose
tolerance in women with PCOS (43).
The cardiovascular effect of these
contraceptives in women with PCOS
is unknown, but they have been associated with a increased risk for cardiovascular arterial events, especially
in older women who smoke (44).
Anovulation

In the Clinic

Table 5. Drug Therapy for PCOS

Agent

Mechanism of Action

Oral contraceptive

Reduces ovarian
Depends on
androgen production, formulation
decreases LH
production

Spironolactone

Androgen-receptor
inhibitor

50200 mg/d

Cyproterone
acetate

Androgen-receptor
inhibitor

Finasteride

5-alpha-reductase
inhibitor that
reduces peripheral
conversion of
testosterone into
DHT (active
metabolite on
the skin)
Blocks ornithine
decarboxylase
(required for growth
and differentiation
of the hair follicle)
Insulin sensitizer
(primarily at
the liver)

2550 mg/d
Potent antiandrogen
on day 110
agent
of menstrual
cycle or 2 mg/d
in combination
with oral
contraceptive
5 mg/d
Potent antiandrogen
agent

Eflornithine

Metformin

Dosage

Benefits

Side Effects

Notes

Provides menstrual
regularity and
reduces hyperandrogenic manifestations
while providing
contraception; longterm benefits in PCOS
may include improved
body composition and
insulin sensitivity and
lower free testosterone
levels compared with
nonusers
Improves hyoerandrogenic
manifestations

Same as with all oral

contraceptives; more
breakthrough bleeding
occurs with lower-dose
preparations; potential
for worsening insulin
resistance

Choose oral contraceptives

with the least androgenicity;
preparations that combine the
antiandrogen cyproterone
acetate with ethinyl estradiol
are available in some countries
(not the U.S.)

Hyperkalemia, breast
tenderness, breakthrough
bleeding; contraception
is required because of
the potential for
feminization of male
infants
Abnormal liver funcNot available in U.S.
tion tests; delayed menses
for 23 days if on oral
contraceptive; contraception is required because
of the potential for feminization of male infants
Contraception is required
because of the potential for
feminization of male infants

Topical
cream bid

Slows hair growth

everywhere or just
on face

Acne, pseudofolliculitis
barbae

5001000 mg
bid

Improves glucose
tolerance, promotes
weight loss, may restore
menstrual regularity, may
improve clinical response
to clomiphene in obese
women; improves healthrelated quality of life,
emotional distress, and
sexuality; may also reduce
testosterone levels

GI upset, potential
for lactic acidosis
(although this population
usually not at risk),
long-term consequences
not known

Most, but not all, evidence

suggests a benefit with
metformin; all studies have
been small, have had a short
follow-up (6 mo), have
included only obese patients,
and/or have lacked placebo
control; larger long-term
studies are necessary; fertility
may be restored, so it is
important that appropriate
contraception is used if pregnancy is not desired

bid = twice daily; DHT = dihydrotestosterone; GI = gastrointestinal; LH = luteinizing hormone; PCOS = the polycystic ovary syndrome.

44. Baillargeon JP, McClish DK, Essah PA,

Nestler JE. Association between the
current use of lowdose oral contraceptives and cardiovascular arterial disease:
a meta-analysis. J
Clin Endocrinol
Metab.
2005;90:3863-70.
[PMID:15814774]

The use of metformin, a biguanide

drug used to treat type 2 diabetes, is
increasingly common in the treatment of PCOS, although it is not approved by the U.S. Food and Drug
Administration for this indication.
Insulin sensitizers, such as metformin,

seem to improve ovulation and restore

menses, and may be appropriate
when there is evidence of insulin resistance. However, according to the
authors of one review, the benefits
may not be so significant (45). The
wide range of benefits in metabolic,

2011 American College of Physicians

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Annals of Internal Medicine

In the Clinic

1 February 2011

reproductive, and clinical measures

have been reported from nonrandomized trials with metformin, they
note, and close inspection of results
from the adequately controlled studies
shows that the benefits are modest.
Long-term benefits also remain
unknown (46).
A 2007 Cochrane review found that although oral contraceptive agents improved menstrual pattern and serum androgen levels compared with metformin,
metformin reduced fasting insulin and
lowered triglyceride levels better than oral
contraceptives (47). Data were very limited
on the development of cardiovascular disease, endometrial cancer, or diabetes, and
there were no data comparing insulinsensitizing drugs aside from metformin
and oral contraceptives. There is no consensus on predictors of response or on the
recommended dose, including whether
the dose should be based on body weight
and other factors (13).

When insulin sensitizers are prescribed, it is important to tell

women explicitly that their likelihood of ovulation is increased, and
thus so is fertility. This is particularly important if pregnancy is not
desired. Sexually active women
with PCOS may become pregnant,
even if they are not menstruating
regularly and especially if they are
successfully losing weight or being
treated with insulin sensitizers.
When fertility is the primary
concern, which treatment options
are available?
Up to 74% of women with PCOS
have infertility issues (16). Many
women with infertility related to
PCOS can be treated successfully.
Treatment includes lifestyle modifications, including weight loss if needed,
and the antiestrogen medication
clomiphene citrate (48). Because of
the nature of the condition, older
women with PCOS may have superior ovarian reserves as they age (49).
Clomiphene is an estrogen-like
hormone that acts to increase levels
of FSH and LH and improves the
chances of ovulation. Sometimes

1 February 2011

Annals of Internal Medicine

clomiphene is used in combination

with insulin sensitizers, such as
metformin; however, a recent randomized clinical trial did not show
a benefit of this approach.
In a randomized, controlled trial (RCT), 626
infertile women with PCOS received
clomiphene citrate plus placebo, extended-release metformin plus placebo, or
clomiphene and metformin combined until pregnancy was confirmed or 6 months
had passed (50). The conception rate
among women who ovulated was lower
in the metformin group (21.7%) than in the
clomiphene group (39.5%; P=0.002) or in
the combination-therapy group (46.0%,
P<0.001). Rates of first-trimester pregnancy loss were similar among the groups. The
live-birth rate was 22.5% (47 of 209 participants) in the clomiphene group, 7.2% (15
of 208) in the metformin group, and 26.8%
(56 of 209) in the combination-therapy
group (P<0.001 for metformin vs. both
clomiphene and combination therapy; P =
0.31 for clomiphene vs. combination therapy). The investigators concluded that
clomiphene was superior to metformin in
achieving live birth, although multiple
births was a complication (occurring in
6.0% in the clomiphene group vs. 0% in the
metformin group and 3.1% in the combination-therapy group).

A recent Cochrane review found little evidence that metformin improves live-birth
rates in women with PCOS, whether it is

45. Harborne L, Fleming

R, Lyall H, Norman J,
Sattar N. Descriptive
review of the evidence for the use of
metformin in polycystic ovary syndrome. Lancet.
2003;361:1894-901.
[PMID:12788588]
46. Driscoll DA. Polycystic ovary syndrome
in adolescence.
Semin Reprod Med.
2003;21:301-7.
[PMID:14593553]
47. Costello M, Shrestha
B, Eden J, Sjoblom P,
Johnson N. Insulinsensitising drugs
versus the combined oral contraceptive pill for hirsutism, acne and risk
of diabetes, cardiovascular disease, and
endometrial cancer
in polycystic ovary
syndrome. Cochrane
Database Syst Rev.
2007 Jan
24;(1):CD005552.
[PMID:17253562]
48. Thessaloniki
ESHRE/ASRM-Sponsored PCOS Consensus Workshop
Group. Consensus
on infertility treatment related to
polycystic ovary syndrome. Hum Reprod.
2008;23:462-77.
[PMID:18308833]
49. Hudecova M, Holte
J, Olovsson M Sundstrm Poromaa I.
Long-term follow-up
of patients with
polycystic ovary syndrome: reproductive
outcome and ovarian reserve Hum Reprod. 2009;24:117683. [PMID:19168874]
50. Legro RS, Barnhart
HX, Schlaff WD, et al.
Clomiphene, metformin, or both for
infertility in the polycystic ovary syndrome. N Engl J
Med. 2007;356:55166. [PMID:17287476]

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2011 American College of Physicians

Another RCT, which included 171 women

with PCOS, randomized those with BMI
>32 kg/m2 to receive placebo (standard
care) or metformin and women with BMI
32 kg/m2 to receive clomiphene citrate
(CC standard care), metformin, or both
(51). For the women with BMI >32 kg/m2,
the clinical pregnancy and live-birth rates
by 6 months were 22% (7 of 32 participants) and 16% (5 of 32), respectively, with
metformin, and 15% (5 of 33) and 6% (2 of
33), respectively, with placebo. For women
with BMI 32 kg/m2, the clinical pregnancy and live-birth rates were 40% (14 of 35)
and 29% (10 of 35) with metformin, 39%
(14 of 36) and 36% (13 of 36) with CC, and
54% (19 of 35) and 43% (15 of 35) with
combination metformin plus CC. The investigators concluded that metformin provided no benefit to standard care, and
noted that pregnancy and live-birth rates
were low in women with BMI >32 kg/m2
regardless of the treatment.

In the Clinic

used alone, combined with clomiphene, or

compared with clomiphene (52). The reviewers, who analyzed 31 trials (2537
women), 27 of which used metformin
(2150 women), concluded that its use is
limited in improving reproductive outcomes in women with PCOS.

Women who are insensitive to

clomiphene may be treated with gonadotrophins or laparoscopic ovarian
surgery to prompt ovulation. Gonadotrophins can effectively improve
fertility; however, a frequent result in
women with PCOS is overproduction of follicles, leading to the ovarian hyperstimulation syndrome and
multiple pregnancies.

51. Johnson NP, Stewart

AW, Falkiner J, et al.
PCOSMIC: a multicentre randomized
trial in women with
polycystic ovary syndrome evaluating
metformin for infertility with
clomiphene. Hum
Reprod.
2010;25:1675-83.
[PMID:20435692]
52. Tang T, Lord JM, Norman RJ, et al. Insulinsensitising drugs
(metformin, rosiglitazone, pioglitazone,
D-chiro-inositol) for
women with polycystic ovary syndrome, oligo amenorrhoea and
subfertility.
Cochrane Database
Syst Rev. 2010 Jan
20;(1):CD003053.
[PMID:20091537]
53. Bayram N, van Wely
M, Kaaijk EM,
Bossuyt PMM, van
der Veen F. Using an
electrocautery strategy or recombinant
FSH to induce ovulation in polycystic
ovary syndrome: a
randomised controlled trial. BMJ.
2004;328:192-5.
[PMID:14739186]
54. Farquhar C, Vandekerckhove P, Lilford R.
Laparoscopic
drilling by
diathermy or laser
for ovulation induction in anovulatory
polycystic ovary syndrome. Cochrane
Database Syst Rev
2005;(3):CD001122.
[PMID:17636653]

2011 American College of Physicians

Laparoscopic ovarian surgery, commonly referred to as laparoscopic

ovarian drilling (LOD), is an alternative that does not trigger ovarian hyperstimulation or the chances
of multiple pregnancy.
A multicenter study from the Netherlands
randomized 168 patients resistant to
clomiphene to either laparoscopic ovarian
diathermy (electrocautery; n = 83) or induction of ovulation with recombinant FSH (n =
85). After 6 months, the initial cumulative
pregnancy rate was 34% in the diathermy
group compared with 67% with FSH. The
women who did not ovulate after diathermy
received clomiphene and FSH, resulting in a
similar cumulative pregnancy rate in each
group (67%) by 12 months (53).
A Cochrane review found similar rates of
live birth and miscarriage in women with
clomiphene-resistant PCOS undergoing
gonadotrophin treatment and LOD (54).
They concluded that LOD provides the advantage of a reduced rate of multiple pregnancies; however, they noted that concerns exist regarding possible long-term
effects of LOD on ovarian function.

Women with PCOS who are obese

may have a particularly difficult time
getting pregnant and should be encouraged to pursue moderate weight
loss to improve reproductive function. Obesity can also make fertility
treatment more difficult to monitor
because it makes it harder to see the
number of developing follicles in the
ovaries, and this can increase the risk

ITC2-12

In the Clinic

for multiple ovulation and multiple

pregnancy (13).
Infertility treatment generally calls
for a specialist. Clinicians should
refer patients to a reproductive endocrinologist or an infertility specialist for treatment. A full infertility
work-up of both partners should be
done before drug therapy is initiated.
What are the treatment options
for hirsutism?
Excess hair growth can have both
physical and psychological effects on
women. When hirsutism is the major
sign, some women prefer nonsystemic
therapy if an acceptable cosmetic result can be achieved. Local measures
for hair removal include shaving, waxing, depilatories, lasers, and electrolysis, depending on personal preference,
location, and extent of hair growth.
Topical eflornithine cream can effectively retard hair growth and may be
combined with laser treatment or other measures of hair removal (42).
With severe hirsutism, it is usually
necessary to combine systemic and
nonsystemic therapies to achieve
good results. Oral contraceptives are
widely prescribed for hirsutism as well
as acne. The antiandrogen agent
cyproterone, in combination with oral
contraceptives, is considered one of
the most effective treatments of hirsutism; however, common side effects
include reduced libido, tiredness, and
liver function changes (7). Hirsutism
is slow to respond to therapy, and a
minimum of 6 months is required to
assess effectiveness.
There is some evidence that insulinsensitizing agents might improve
hirsutism and acne because insulin resistance affects both disorders; however, use of these drugs for cosmetic
purposes is not recommended (45).
What are the risks for prolonged
amenorrhea, and are there
interventions to minimize these risks?
Several disorders that are common in
women with PCOS, including obesity, hyperinsulinemia, diabetes,

Annals of Internal Medicine

1 February 2011

anovulatory cycles, and high androgen levels, are associated with an

increased risk for endometrial carcinoma (55). Women with PCOS have
elevated estrogen levels that cause endometrial proliferation and, thus, increase risk for endometrial carcinoma.
Clinicians should encourage
women to report >3 months of
amenorrhea so that a progesterone
challenge can be given, if appropriate. In women with PCOS who
have not had menstrual bleeding
for 1 year, endometrial biopsy may
be warranted (56).
When deciding whether to obtain
a biopsy, it may be useful to order an
ultrasound to measure endometrial
thickness (57). The role of ultrasound measurements of endometrial
thickness to diagnose endometrial
cancer in premenopausal women is
unclear. Consider office biopsy if the
endometrium is >14 mm.
Either cyclic progestin or oral contraceptives with combination estrogen and progestin are used to prevent endometrial proliferation.
Insulin-sensitizing drugs or weight
loss can also effectively increase ovulatory events in women with PCOS.
Does pregnancy in women with
PCOS carry specific risks?
The risk for gestational diabetes and
possibly preeclampsia is increased
during pregnancy in women with
PCOS. Occurrence of the

hyperstimulation syndrome may also

occur if gonadotropins were used to
induce ovulation. Therefore, planning
pregnancy is particularly important for
women with PCOS, so that such risk
factors as diabetes, hypertension, and
obesity can be reduced to the extent
possible before conception and followed carefully throughout the pregnancy. Clinicians should ask women
about their pregnancy plans, discuss
the potential for complications, and
screen for diabetes and hypertension
before they become pregnant.
Medical conditions that are present
before pregnancy should be addressed
in advance to ensure optimal outcomes. It is particularly important for
diabetics to achieve excellent glycemic
control before becoming pregnant to
reduce the risk for congenital anomalies. Antihypertensive therapy may
need to be adjusted before conception, particularly in patients using
angiotensin-convertin enzyme inhibitors. All women (even those
without PCOS) should plan their
pregnancies so that they can receive
proper folate supplementation.
Women at risk for complications
during pregnancy require closer follow-up and more fetal monitoring
throughout the pregnancy. In addition to increased maternal risk, the
fetus is also at increased risk for
neonatal complications, including
preterm birth and neonatal intensive care unit admission (58).

Treatment... Clinicians should encourage patients with PCOS who are overweight
to lose a realistic amount of weight through diet and exercise. Even moderate
weight loss can improve menstrual regularity and ovulatory function, hirsutism,
insulin sensitivity, and response to fertility medication. Drug therapy is aimed at
treating the symptoms of PCOS. If the patient is not seeking pregnancy, an oral
contraceptive agent, sometimes combined with an antiandrogen agent, is commonly used. If the patient is seeking pregnancy, clomiphene is commonly used.
Women with PCOS who are pregnant face an increased risk for complications and
require special attention. An insulin sensitizer, such as metformin, may also be
used to improve symptoms. PCOS may increase risk for endometrial carcinoma.
Clinicians should encourage women to report prolonged amenorrhea so that a
progesterone challenge or endometrial biopsy can be done if needed.

CLINICAL BOTTOM LINE

1 February 2011

Annals of Internal Medicine

In the Clinic

ITC2-13

55. Stoll BA. New metabolic-endocrine risk

markers in endometrial cancer. Br J Obstet Gynaecol.
1999;106:402-6.
[PMID:10430187]
56. Ehrmann DA. Polycystic ovary syndrome. N Engl J
Med. 2005;352:122336. [PMID:15788499]
57. Balen A. Polycystic
ovary syndrome and
cancer. Hum Reprod
Update. 2001;7: 5225. [PMID:11727859]
58. Boomsma CM,
Fauser BC, Macklon
NS. Pregnancy complications in women
with polycystic
ovary syndrome.
Semin Reprod Med.
2008;26:72-84.
[PMID:18181085]
59. Salley KES, Wickham
EP, Cheang KI, Essah
PA, Karjane NW,
Nestler JE. Glucose
intolerance in polycystic ovary syndrome: a position
statement of the Androgen Excess Society. J Clin Endocrinol
Metab.
2007;92:4546-56.
[PMID:18056778]

2011 American College of Physicians

60. American Association of Clinical Endocrinologists Polycystic Ovary

Syndrome Writing
Committee. American Association of
Clinical Endocrinologists Position Statement on Metabolic
and Cardiovascular
Consequences of
Polycystic Ovary
Syndrome. Endocr
Pract. 2005;11:12634. [PMID:15915567]

What do professional organizations

recommend regarding the care of
patients with PCOS?
In a position statement, the Androgen Excess Society recommends that
all women with PCOS be screened
for glucose intolerance with the use
of a glucose-tolerance test at the initial presentation and every 2 years
thereafter. Rescreening should occur
every 2 years for patients with normal glucose tolerance, particularly
those wishing to become pregnant,
and more frequently if there are additional risk factors (59). However,
there does not seem to be a consensus among experts regarding the frequency of screening for women who
are not pregnant or planning to

beome pregnant. Rescreening should

occur annually in patients with impaired glucose tolerance and treated
with lifestyle modification and
weight loss. The authors state that
metformin may be used to treat or
prevent progression to impaired glucose tolerance, but note that it
should not be mandated until there
are well-designed RCTs demonstrating efficacy.
The American Association of Clinical Endocrinologists recommends
in its position statement that metformin should be considered the
initial intervention in most women
with PCOS and in particular in
those are overweight (60).

PIER Modules

In the Clinic

Tool Kit

www.pier.acponline.org
Access the PIER modules on the polycystic ovary syndrome, female
infertility, obesity, and type 2 diabetes. PIER modules provide
evidence-based, updated information on current diagnosis and
treatment in an electronic format designed for rapid access at the
point of care.

Patient Information

The Polycystic
Ovary Syndrome

www.annals.intheclinic/tools
Access copies of the patient information sheet on the following page
for duplication and distribution to patients.
www.nichd.nih.gov/health/topics/Polycystic_Ovary_Syndrome.cfm
Access patient information on PCOS from the NIHs National
Institute for Child Health and Human Development, plus
information on related clinical trials.
www.nlm.nih.gov/medlineplus/ovariancysts.html (English)
www.nlm.nih.gov/medlineplus/spanish/ovariancysts.html (Spanish)
Access patient information in English and Spanish on ovarian cysts
from the National Library of Medicines MEDLINE Plus.

Clinical Guidelines
www.aace.com/pub/pdf/guidelines/PCOSpositionstatement.pdf
Access the position statement on metabolic and cardiovascular
consequences of polycystic ovary syndrome, released in 2005, from
the American Association of Clinical Endocrinologists.
http://jcem.endojournals.org/cgi/content/full/92/12/4546
Access the position statement on glucose intolerance in PCOS,
released in 2007, from the Androgen Excess Society.
www.scribd.com/doc/7269923/PCOSObesity-Pcos-ESHRE-ASRM
-Consensus
Access the 2003 Rotterdam ESHRE-ASRM consensus statement on
diagnostic criteria and long-term health risks related to PCOS

Quality Measures
Development of quality measures for PCOS diagnosis and
management seem to be at an early stage, and Web sites of
professional groups, such as ESHRE, American College of
Obstetrics and Gynecology, Androgen Excess Society, and the
Endocrine Society, should be consulted for the latest information.

2011 American College of Physicians

ITC2-14

In the Clinic

In the Clinic

Practice
Improvement

Annals of Internal Medicine

1 February 2011

THINGS YOU SHOULD

KNOW ABOUT THE
POLYCYSTIC OVARY
SYNDROME

In the Clinic
Annals of Internal Medicine

What is the polycystic ovary syndrome

(PCOS)?
PCOS is a common hormonal disorder affecting 5%
to 10% of women.
Many women dont find out that they have PCOS
until they have difficulty getting pregnant.
Women with PCOS have high levels of hormones
called androgens, which can destabilize normal
ovulation.
Having irregular, infrequent menstrual cycles is a
common symptom of PCOS.
PCOS may cause small cysts to form in the ovary.
These cysts are detected by ultrasonography, an
imaging test that shows the internal organs.

PCOS can occur in women once they go through

puberty.
Symptoms often develop during the first year that
girls start menstruating.
Doctors dont know what causes PCOS. It seems to
run in families, but other factors seem to play a role,
too, such as body weight.
PCOS is more common in overweight women.

What are the symptoms of PCOS?

An oral contraception agent (the pill) can treat

physical symptoms, such as excess hair growth and
make periods more regular. It can be combined with
a drug called an antiandrogen, which prevents or
blocks the effects of too much androgen.
Drugs that trigger ovulation, such as clomiphene,
can improve fertility and help you become pregnant.

Can you get pregnant if you have

PCOS?

Irregular periods or no periods at all.

Infertility.
Excess hair growth on face, chest, and back.
Severe acne, acne that develops in adulthood, or
acne that does not get better when it is treated.
In severe cases, male-pattern hair loss.
Raised, velvety brown discoloration on the nape of
neck, underarms, knuckles, and elbows.

How is it treated?
Losing even a small amount of weight can reduce
symptoms and help your body ovulate more
normally.

Most women who have PCOS are able to become

pregnant.
Your doctor may prescribe a drug called clomiphene
that helps your ovaries to produce eggs.
Lifestyle modifications, including weight loss, smoking cessation, and exercise, can improve fertility and
increase the chances of pregnancy.
Talk to your doctor if you have PCOS and wish to become pregnant. You may benefit from seeing a fertility specialist.

For More Information

www.nichd.nih.gov/publications/pubs/upload/PCOS_booklet.pdf

Comprehensive booklet titled Beyond Infertility: Polycystic

Ovarian Syndrome on understanding PCOS, particularly PCOScaused infertility, from the NIHs National Institute for Child
Health and Human Development.
www.hormone.org/polycystic/

Provides information for patients on PCOS symptoms and

treatment, plus a list of PCOS links, from the Hormone
Foundation, the public education affiliate of The Endocrine
Society.

Patient Information

Who gets PCOS?

CME Questions

1. A 21-year-old woman is evaluated for a

7-year history of oligomenorrhea and
slowly progressive hirsutism. Menses
began at age 14 years and were always
irregular. She has gained weight at a rate
of approximately 4.5 kg (10 lb) per year.
Her facial hair has become progressively
thicker since age 18 years, and she now
menstruates only three to four times per
year. She is sexually active but does not
want to become pregnant at this time.
Family history is noncontributory, and
she takes no medications.

irregular menses. She also notes that her

voice has deepened over the past month.
The patient has not menstruated for the
past 2 months despite having normal
menses previously. Family history is
unremarkable. She takes no medications.

On physical examination, vital signs are

normal, and BMI is 28. Prominent
terminal hairs are noted on the upper lip
and chin, with some on the upper cheeks
and chest; there is thick hair from the
pubis to the umbilicus. Results of a pelvic
examination and Pap smear are normal.

Laboratory studies reveal the following:

follicle-stimulating hormone, 2 mU/mL
(2 U/L); human chorionic gonadotropin,
negative for pregnancy; luteinizing
hormone, 1.2 mU/mL (1.2 U/L); prolactin,
17 ng/mL (17 g/L); testosterone, total,
326 ng/dL (11.3 nmol/L); and thyroidstimulating hormone, 1.1 U/mL
(1.1 mU/L).

Laboratory studies reveal the following

information: dehydroepiandrosterone
sulfate, 4.3 g/mL (11.6 mol/L); human
chorionic gonadotropin, negative for
pregnancy; 17-hydroxyprogesterone,
105 ng/dL (3.15 nmol/L) (normal,
<400 ng/dL [12.0 nmol/L]); prolactin,
11 ng/mL (11 g/L); testosterone, total,
84 ng/dL (2.9 nmol/L); and thyroidstimulating hormone, 1.4 U/mL
(1.4 mU/L). The clinician also tested for
thyroid dysfunction and prolactinomas.
A progestin withdrawal challenge with
medroxyprogesterone acetate results in a
temporary resumption of menses.
Which of the following is the most
appropriate next step in management?

A. Measurement of free testosterone

level
B. Prednisone therapy
C. Spironolactone and oral
contraceptive therapy
D. Transvaginal ovarian ultrasonography
2. A 34-year-old woman is evaluated for a
6-month history of rapidly progressive
hirsutism, a 3-month history of acne and
weight gain, and a 2-month history of

On physical examination, vital signs are

normal, and BMI is 26. There are coarse
hairs on the upper and lower lips, chin,
and sides of her face. Acne is present on
her face and back. She has no
galactorrhea. Pelvic examination reveals
an enlarged clitoris.

A. CT of the abdomen and pelvis

B. Measurement of the serum estradiol
level
C. Measurement of the serum free
testosterone level
D. Progestin withdrawal challenge
3. A 23-year-old woman is evaluated after
having no menses for 6 months. She
began menstruating at age 12 years, and
menses have always been regular. The
patient reports no recent weight gain,
voice change, or facial hair growth; she
says she may even have lost some weight
recently and tends to feel warm. She is
not sexually active. There is no family
history of infertility or premature
menopause.
On physical examination, temperature is
normal, blood pressure is 115/72 mm Hg,
pulse rate is 66/min, respiration rate is
14/min, and BMI is 22. She has no acne,
hirsutism, or galactorrhea. Her thyroid
gland is slightly enlarged. Visual field
testing yields normal results.

Results of standard laboratory studies are

normal, including thyroid-stimulating
hormone and free thyroxine (T4) levels; a
human chorionic gonadotropin level is
negative for pregnancy.
Which of the following is the most
appropriate first step in evaluation?

A. Hysterosalpingography
B. Measurement of serum folliclestimulating hormone and prolactin
levels
C. Measurement of total serum
testosterone level
D. D Pelvic ultrasonography
4. A 26-year-old woman is evaluated for a
4-month history of amenorrhea. Menses
began at age 13 years. At age 18 years,
the patient was placed on an oral
contraceptive pill to control heavy
bleeding. She discontinued the oral
contraceptive pill 4 months ago because
she and her husband want to become
pregnant, and she has had no menses
since then. There is no family history of
infertility or premature menopause.
On physical examination, vital signs are
normal, and BMI is 24. There is no acne,
hirsutism, or galactorrhea. Examination
of the thyroid gland and visual field
testing yield normal findings. Pelvic
examination findings are also normal. An
office pregnancy test is negative.
Laboratory studies reveal the following:
follicle-stimulating hormone, 2 mU/mL
(2 U/L); prolactin, 17 ng/mL (17 g/L);
thyroid-stimulating hormone, 1.1 U/mL
(1.1 mU/L); and thyroxine (T4), free,
1.0 ng/dL (12.9 pmol/L).
Which of the following is the most
appropriate next diagnostic test?

A. Measurement of the plasma

dehydroepiandrosterone sulfate level
B. Measurement of serum estradiol level
C. MRI of the pituitary gland
D. Progestin withdrawal challenge

Questions are largely from the ACPs Medical Knowledge Self-Assessment Program (MKSAP, accessed at
http://www.acponline.org/products_services/mksap/15/?pr31). Go to www.annals.org/intheclinic/
to complete the quiz and earn up to 1.5 CME credits, or to purchase the complete MKSAP program.

2011 American College of Physicians

ITC2-16

In the Clinic

Annals of Internal Medicine

1 February 2011